ANTIGOITROGENIC AND CALORIGENIC ACTIVITIES OF THYROXINE ANALOGUES IN RATS1

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Abstract
The relative potencies of more than forty thyroxine analogues and a soluble hog thyroglobulin extract were established in parallel goiter-prevention and calorigenic assays against the same thyroxine standard. By both methods of assay twelve of the preparations had activities ranging from 5% to 800% of that of thyroxine. The activities, if any, of the remaining analogues were less than 3% of that of the standard. Analysis of area-under-curve and speed of response in calorigenic assays indicated that all the active analogues and soluble thyroglobulin were qualitatively similar with respect to this parameter of thyromimetic function in normal adult male rats. Thyroglobulin was characteristically more active than expected when its potency, relative to thyroxine, was calculated on the assumption that its thyronine-bound iodine, as determined by the Blau, 1935, procedure, was in the form of thyroxine. Correlations of structural changes with corresponding assay activities indicated the following generalizations: (a) analogues having an intact alanine side chain required iodine substituents at least in the 3 and 5 positions as a condition for biological activity. Thyronines having iodine substituents in the 3, the 3 and 3[image], or the 3,3[image] and 5[image] positions were biologically inactive at relatively high dose levels; (b)the potency of analogues were deaminated side chains decreased as the chain length increased from two to four carbons; (c) analogues having a deaminated side chain required iodine substituents in the 3 and 5 positions with additional iodine substitution in either or both the 3[image] and 5[image] positions, as a condition for biological activity, but 3,5,3[image]-triiodo compounds were not necessarily more active than the corresponding 3,5,3[image], 5[image]-tetraiodo derivatives; (d) inactive 3,5-diiodothyropropionic acid was activated by introduction of methyl groups in positions 3[image] and 5[image]; (e) replacement of the phenolic hydroxyl group at the 4.

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